Project Abstract/Summary An often overlooked, yet increasingly common, behavior in elderly populations is alcohol consumption. In fact, >40% of those over 65 years of age drink alcohol. The majority of older people are not misusing alcohol, rather have a drink or two per day, up to four times a week, placing them into the category of moderate drinkers. Misuse of alcohol is associated with increased systemic inflammation, yet reduced cellular and humoral immunity, ultimately leading to increased mortality after infection in alcohol abusers. In addition, the elderly experience greater prevalence, mortality, and complications caused by pathogens such as Streptococcus pneumoniae. The underlying immune dysfunction predisposing older individuals to infection is at least partly attributed to the effects of low-grade chronic inflammation that increases with age, termed inflamm-aging. Thus, as both inflamm-aging and alcohol consumption independently have a negative impact on innate immune cells, investigating how alcohol influences immunity in the elderly merits further study. Two critical effector cells in the context of S. pneumoniae infection are alveolar macrophages and neutrophils, and both are functionally diminished with advanced age and alcohol misuse independently. Preliminary data suggest that alveolar macrophages from aged animals given ethanol are impaired in their ability to initiate inflammation in the lungs, and these animals experience a compensatory increase in pulmonary neutrophil recruitment. However, neutrophils from aged animals are unable to leave the pulmonary vasculature and enter the infected airways to contribute to pathogen clearance. From this evidence, we hypothesize that inflamm-aging and alcohol-mediated changes in alveolar macrophage and neutrophil function cause more pulmonary neutrophil recruitment, yet an impaired ability of neutrophils to enter the infected airways, ultimately leading to enhanced morbidity and mortality in aged mice given alcohol. In vivo manipulation of macrophage and neutrophil phenotype in aged mice given alcohol will improve the pulmonary immune response to infection. To test this, in Aim 1, we will assess the independent and combinatorial effects of advanced age and alcohol consumption on macrophage functions. Moreover, we will determine whether changes in alveolar macrophages are necessary and sufficient in driving aberrant neutrophil recruitment in aged mice given alcohol. In Aim 2, we will examine the critical receptors and signaling pathways involved in neutrophil exit from the vasculature and entry into the airways. Furthermore, we will define if these changes are due to direct changes in neutrophils imparted by aging and alcohol consumption, and try to enhance their ability to navigate their way into the infected airway. Taken together, these studies will fill a critical gap in knowledge in understanding the immunological impact of alcohol consumption in the elderly. We expect data generated from these studies will lay the foundation for future mechanistic studies and identify putative targetable pathways for clinical interventions in a population already at-risk for infection-mediated complications and mortality.